This research program will use pedigreed baboons to study the interaction of diet and genotype in determining lipoprotein phenotypes. A colony of 25 male and 150 female breeders are mated to produce optimally structured pedigrees for specialized analyses that allow the testing of various genetic hypotheses. Specific nonrandom matings between relatives also are used to enable detection of recessive alleles that are uncommon in the population at large. The long-term goal is to identify individual genes that contribute to variation in lipoprotein phenotypes and to determine the genotype-genotype and genotype-diet interactions involved in determining lipoprotein phenotypes. More specifically, we will determine whether the same genes or different genes modulate the cholesterolemic responses to dietary cholesterol and to dietary saturated fatty acids. Baboons are phylogenetically related and physiologically similar to humans. Their use as an animal model enables controlled genetic and experimental manipulations, and facilitates the detection of genetic effects and interactions that may be difficult to identify in humans. The results can lead to new hypotheses that can be tested with human subjects. Conversely, baboons are useful for testing certain hypotheses that arise from research with human subjects, but that can be tested only in an animal model. Project 1 will use complex segregation analysis and related statistical genetic techniques to detect major genes that affect lipoprotein phenotypes in pedigreed baboons, to detect pleiotropic effects of those genes on lipoproteins, and to determine how those genes interact with genetic background and dietary factors (fat and cholesterol). Project 2 will use linkage and measured genotype analysis (i.e., association studies) to locate major genes, and to determine pleiotropic, epistatic, and dietary interaction effects of candidate loci on lipoprotein phenotypes. Project 3 will determine the molecular bases of the effects of candidate locus genotypes on aspects of lipoprotein phenotypes; the research proposed for years 11-15 will focus on the loci for apo(a) and LCAT. The research projects are supported by core units for lipid and lipoprotein biochemistry, data management and computing, veterinary services, and administration.